Hepatitis E virus (HEV) is the etiologic agent responsible for large outbreaks of clinical hepatitis in developing countries and a large proportion of sporadic clinical hepatitis in developing countries. Despite its omnipresence, the mechanism for maintenance of inter-epidemic HEV in populations remains poorly understood. The recent discoveries of a large zoonotic reservoir for the virus, food-bornetransmission of HEV via contaminated meat products, and substantial HEV seroprevalence in industrialized countries have reinforced how little is known about the epidemiology of HEV. In this application we propose to test stored serum samples collected as a part of the third National Health and Nutrition Survey (NHANES III)for the presence of anti-HEV IgG using a highly accurate and validated ELISA assay developed at the Hepatitis Viruses Section, National Institutes of Health (NIH). NHANES III was a representative survey of the entire non-institutionalized United States population conducted from 1988-94 by the Centers for Disease Control and Prevention (CDC) and included detailed assessment of demographic, occupational, and food consumption characteristics of its participants. All anti-HEV testing will be conducted at the Johns Hopkins Infectious Disease Program (IDP) laboratories using the NIH assay. We will validate our results via a 2% sample re-testing at the Hepatitis Virus Section, NIH, and conduct interim analyses in collaboration with the National Center for Health Statistics, CDC and the Division of Viral Hepatitis, CDC. We expect the results of the proposed project to give a precise estimate of overall HEV antibody prevalence in the United States, as well give substantial insight into rates of disease exposure among various age, gender, and racial/ethnic groups. Additionally, we expect to have excellent power to conclusively test postulated epidemiologic associations between HEV seropositivity and contact with animals, meat consumption, and socioeconomic status. This project will produce the most comprehensive assessment of HEV epidemiology available to date, and will aid in the identification of at-risk groups that may benefit from the newly developed and highly efficacious HEV vaccine.